PT2066669E - Adenosine derivatives as a2a receptor agonists - Google Patents

Description

ΡΕ2066669

DESCRIPTION " ADENOSIN DERIVATIVES AS A2A RECEPTOR AGONISTS "

This invention relates to organic compounds, their preparation and their use as pharmaceuticals.

In one aspect the invention provides compounds of formula (Ia), or stereoisomers or pharmaceutically acceptable salts thereof,

(la) in which R 1 and R 1b are independently selected from a 3- to 12-membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other hetero-2, P 2066669 atoms selected from the group consisting of by oxygen and sulfur, said group being optionally substituted with oxo, O-C 1 -C 6 alkyl, C 6 -C 10 aryl, R 1 c or optionally substituted C 1 -C 8 alkyl, or R 1 and R 1 b are independently selected from -NR 4 R 4, and -NR5-C1 -C6 alkylcarbonyl; R 2 is C 1 -C 8 alkyl optionally substituted with OH, halogen C 6 -C 10 aryl optionally substituted with OH, S-C 1 -C 6 alkyl, CN, halogen, O-C 7 -C 14 aralkyl, or O-C 1 -C 6 alkyl, a carbocyclic group C3 -C15 -alkyl optionally substituted with O-C7 -C14 aralkyl, a C3 -C15 carbocyclic group, O-C1 -C6 alkyl, C2 -C8 alkenyl, C2 -C8 alkynyl or C1 -C8 alkyl, -SO2-C8-C8 alkyl, a 3- to 12-membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing further 1-4 heteroatoms selected from the group consisting of oxygen and sulfur, which group is optionally substituted with a 3- to 12-membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing further 1-4 heteroatoms selected from the group consisting of oxygen and sulfur, C7 -C14 aralkyl, or substituted C6 -C14 aryl optionally with C7-C14-aralkyl, or R3 is hydrogen, halo, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or C 1 -C 8 alkoxycarbonyl, or R 3 is C 1 -C 8 alkylamino optionally substituted with OH, R 1, amino, di (C 1 -C 8) alkylamino, -NH-C ( = O) -C1 -C8 alkyl, -NH-SO2 -C1 -C8 alkyl, -NH-C (= O) -NH-R3c, -NH-C (= O) -NH- (C1 -C3) alkyl-R3, a C 3 -C 15 carbocyclic or C 6 -C 10 aryl group optionally substituted with C 6 -C 10 aryloxy, or R 3 is a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other hetero atoms selected from the group consisting of oxygen and sulfur, which group is optionally substituted with 0-3 R4; R and R are each independently a 3- to 12-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; optionally substituted with halo, cyano, oxo, OH, carboxyl, nitro, C1 -C6 alkyl, C1 -C6 alkylcarbonyl, OH-C1 -C6 alkyl, C1 -C8 haloalkyl, C1 -C8 aminoalkyl, amino (OH) -C1 -C6 alkyl or C1 -C6 alkoxy optionally substituted with aminocarbonyl; R 3c is a 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur which is optionally substituted with a 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from from the group consisting of nitrogen, oxygen and sulfur; R3d are independently a 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, a 5- or 6-membered heterocyclic group which is optionally substituted with halo, cyano, oxo , OH, carboxy, amino, nitro, C1 -C6 alkyl, C1 -C8 alkylsulfonyl, aminocarbonyl, C1 -C8 alkylcarbonyl, C1 -C8 alkoxy optionally substituted with aminocarbonyl, or a 5- or 6-membered heterocyclic ring containing at least one heteroaromatic ring selected from the group consisting of nitrogen, oxygen and sulfur, which ring is also optionally substituted with halo, cyano, oxo, OH, carboxy, amino, nitro, C 1 -C 8 alkyl, C 1 -C 4 alkylsulfonyl, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkoxy optionally substituted with aminocarbonyl; R4 is selected from OH, C1 -C8 alkyl optionally substituted with OH, C1 -C6 alkoxy, C7 -C14 aralkyl optionally substituted with OH, O-C1 -C8 alkyl, C6 -C10 haloaryl, or O-C6 -C10 aryl, C 1 -C 8 alkoxy, C 6 -C 10 aryl optionally substituted with OH, C 1 -C 8 alkyl, O-C 1 -C 8 alkyl or -halo, O-C 6 -C 10 aryl optionally substituted with OH, C 1 -C 8 alkyl, C8 alkyl or -halo, and NR4 C (O) NR9 R4 h; R4f, R4h are independently H, or C1-C8alkyl; R4g is a 3- to 12-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; and A is selected from 6 ΡΕ 2066669

(I.e.

Definitions

The terms used in the specification have the following meanings: " Optionally substituted " means that the group to which reference may be in one or more of its positions any one or any combination of the substituents that are listed below in the definition. " Halo " or " halogen " as used herein may be fluoro, chloro, bromo or iodo. Preferably halo is chloro. " Hydroxyl " as used herein is OH. ΡΕ 2066669 7 " C 1 -C 8 alkyl " as used herein denotes a straight chain or branched alkyl containing 1-8 carbon atoms. Preferably C 1 -C 6 alkyl is C 1 -C 4 alkyl. " C 1 -C 6 -alkoxy " as used herein denotes straight or branched chain alkoxy groups containing 1-8 carbon atoms (for example O-C 1 -C 6 alkyl). Preferably, the C1-C8 alkoxy will be a C1 -C4 alkoxy. " Cycloalkyl C3-C8 " as used herein denotes a cycloalkyl containing 3-8 ring carbon atoms, for example a monocyclic group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclo -octyl, any of which may be substituted with one or more, usually with one or two, C1 -C4 alkyl groups; or a bicyclic group, such as bicycloheptyl or bicyclooctyl. " C 1 -C 8 alkylamino " and " di (C1 -C8 alkyl) amino " as used herein denote amino substituted respectively with one or two C1-6 alkyl groups as defined hereinbefore, may be the same or different. ΡΕ2066669 " C 1 -C 6 -alkyl-carbonyl " and " C 1 -C 6 -alkylcarbonyl " as used herein denote respectively C 1 -C 6 alkyl or C 1 -C 6 alkoxy as defined hereinbefore, attached by a carbon atom to a carbonyl group . " C6 -C10 aryl " as used herein denotes a monovalent aromatic carbocyclic group containing 6-10 carbon atoms and which may be, for example, a monocyclic group such as phenyl; or a bicyclic group, such as naphthyl. " C7 -C14 aralkyl " as used herein denotes an alkyl, for example a C 1 -C 4 alkyl, as defined hereinbefore, substituted with C 1 -C 10 aryl as defined hereinbefore. Preferably, the C7 -C14 aralkyl is C7 -C10 aralkyl, such as phenyl C1 -C4 alkyl. " C 1 -C 6 -alkylaminocarbonyl " and " C 3 -C 8 cycloalkylaminocarbonyl " as used herein denote respectively C 1 -C 8 alkylamino and C 3 -C 8 cycloalkylamino as defined hereinbefore, attached by a carbon atom to a carbonyl group. Preferably C1 -C6 alkylaminocarbonyl and C3 -C8 cycloalkylaminocarbonyl are respectively C1 -C4 alkylaminocarbonyl and C3 -C8 cycloalkylaminocarbonyl. " C 3 -C 15 carbocyclic group " as used herein denotes a carbocyclic group having 3-15 ring carbon atoms, for example a monocyclic group, either aromatic or non-aromatic, such as cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or phenyl; or a bicyclic group such as bicyclooctyl, bicyclononyl, bicyclodecyl, indanyl or indenyl, and again any of which may be substituted with one or more, usually one or two, C 1 -C 4 alkyl groups. Preferably the C 3 -C 15 carbocyclic group will be a C 5 -C 10 carbocyclic group, in particular phenyl, cyclohexyl or indanyl. The C 5 -C 15 carbocyclic group may be unsubstituted, or substituted. Included in the substituents on the heterocyclic ring are halo, cyano, OH, carboxy, amino, aminocarbonyl, nitro, C 1 -C 10 alkyl, C 1 -C 10 alkoxy and C 3 -C 10 cycloalkyl. " A 3- to 12-membered heterocyclic ring containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur " as used herein, " pyrazine, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, piperidine, pyrazine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperazine, pyrrolidine, morpholine, triazine, oxazine or thiazole. Preferred heterocyclic rings include piperazine, pyrrolidine, morpholino, imidazole, isotriazole, pyrazole, tetrazole, thiazole, triazole, thiadiazole, pyridine, piperidine, pyrazine, furan, oxazole, isoxazole, oxadiazole and azetidine. The 3- to 12-membered heterocyclic ring may be unsubstituted or substituted.

Throughout this specification and the claims that follow, unless the context implies otherwise, the word " includes ", or its variants, such as " includes " or " including " shall be understood to imply the inclusion of an identified integer or a step, or a group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps. As is known to those skilled in the art, only combinations of substituents that are chemically possible are embodiments of the invention.

Specific compounds of formula (I) which are especially preferred are those which are described hereinafter in the Examples. 11 ΡΕ2066669

Stereoisomers are those compounds in which there is an asymmetric carbon atom. The compounds exist in individual, optically active isomeric forms, or as mixtures thereof, for example in the form of diastereomeric mixtures. The present invention includes both the optically active R and S isomers as well as mixtures thereof. Individual isomers can be separated by methods well known to those skilled in the art, for example, by chiral high performance liquid chromatography (HPLC).

Tautomers are the individual isomers of two or more, which exist in equilibrium and easily convert from one isomeric form to another.

The compounds of the invention may exist in either unsolvated or solvated forms. The term " solvate " is used herein to describe a molecular complex including the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term " hydrate " is employed when said solvent is water.

According to formula (I), R 1a and R 1b are independently suitably a 3 to 12 membered, N-linked, heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur, which group is optionally substituted by oxo, O-C 1 -C 6 alkyl, C 1 -C 10 aryl, R 1 c, or by C 1 -C 8 alkyl optionally substituted with OH. The 3- to 12-membered heterocyclic groups are preferably 5- to 6-membered heterocyclic groups (for example, tetrazole groups, pyrrole groups, pyrazole groups, pyridine groups, isoxazole groups, groups, triazole groups or hydantoin groups). The heterocyclic groups R 1a and R 1b can be attached via N when possible. The heterocyclic groups are preferably substituted with at least one group selected from C 1 -C 8 alkyl optionally substituted with OH (for example, an ethyl group, a hydroxymethyl group or a hydroxyethyl group). These substituent groups of the heterocyclic groups may be C- or N-linked to the heterocyclic group, where possible.

According to formula (I), R1a and R1b are also independently and suitably -NH- C1 -Cs alkylcarbonyl or -NH- (C3 -C8) -alkylcarbonylcarbonyl. The -NH- (C1 -C6) alkylcarbonyl group is preferably an acetamide group or a propionamide group. The -NH-C 3-8 cycloalkylcarbonyl group is preferably a cyclobutane carboxylic acid amide group.

According to formula (I), R2 is suitably H, C1 -C6 alkyl optionally substituted with OH, halogen or C2 -C10 aryl optionally substituted with OH or with O-C1 -C6 alkyl. When substituted, the C1 -C6 alkyl group is suitably substituted with OH, phenyl, naphtha, or preferably with two phenyl groups. When the C1 -C6 alkyl is substituted with two phenyl groups, either or both of the phenyl groups are preferably unsubstituted, or are substituted with at least one OCH3, an OH or a halogen.

According to formula (I), R2 is also suitably C1 -C6 alkyl substituted with a phenyl. This phenyl may also be substituted with a phenyl, wherein this phenyl is substituted with CN, halogen, or C 1 -C 8 -alkyl.

According to formula (I), R2 is suitably a C3 -C15 carbocyclic group (for example, a fluorene group).

According to formula (I), R 3 is suitably selected from amino substituted with R 3c, -R 3c-C 7 -C 14 aralkyl, C 1 -C 8 alkyl optionally substituted with R 3c, and a C 3 -C 15 carbocyclic group optionally substituted with OH, C1 -C6 alkyl or C1 -C6 alkoxycarbonyl. R 3c is suitably a 3- to 12-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur (for example, a pyrrolidine or a pyrazole) optionally substituted with halo, cyano, oxo, OH, carboxyl, nitro, C1 -C6 alkyl, C1 -C6 alkylcarbonyl, OH-C1 -C6 alkyl, C1 -C6 haloalkyl, amino C1 -C6 alkyl, amino (OH) -C1 -C12 alkyl and substituted C1 -C6 alkoxy 14 ΡΕ2066669 optionally with aminocarbonyl. Preferably the 3 to 12 membered heterocyclic group is substituted with at least one C 1 -C 8 alkyl group.

According to formula (I), R 3 is also independently and suitably a 3 to 12 membered heterocyclic group linked by an N atom containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur . This heterocyclic group is preferably a pyrrolidine, a pyrazole, a triazole, a tetrazole or an imidazole. The heterocyclic group is optionally substituted with NR4fC (O) NR4gR4h, NR4aR4b, NHC (O) R20q and R4a and R4b are preferably H or C1-C6 alkyl (e.g. methyl), and R4f and R4h are preferably H. R4g is preferably a 3- to 12-membered heterocyclic group such as pyridine.

According to formula (I), R 3 is also suitably C 6 -C 10 aryl optionally substituted with OH, C 1 -C 8 alkyl, O-C 1 -C 8 alkyl, SO 2 R 10 or -halogen, wherein R 10 is suitably NH 2.

According to formula (I), A is suitably selected from -E-NR14-, -E-NR14-G-NR14-, -E-NR14 C (O) NR14-G-NR14, -E-NR14 C ) G-NR15-, -E-NR14-G-NR14-Ea-, E is suitably selected from 5-6 membered heterocyclic groups such as pyrrolidine and piperidine. Ea is suitably a C3 -C15 carbocyclic group, such as cyclohexyl. Each R 14 is suitably and independently selected from H and C 1 -C 18 alkyl, such as methyl. G is suitably a C 3 -C 15 carbocyclic group optionally substituted with HO 2 or C 1 -C 6 alkyl, or G is suitably selected from 5-6 membered heterocyclic groups such as pyrrolidine and piperidine. Preferably the C 3 -C 15 carbocyclic group will be unsubstituted.

SYNTHESIS

Another embodiment of the present invention provides a process for the preparation of compounds of formula (I) in free form or a pharmaceutically acceptable salt which comprises the steps in which: (i) reacting a compound of formula (II)

wherein ΡΕ 2066669 16 1 to 11, O, R, R, R, U, U 2 are as defined hereinbefore; and T is an leaving group, with a compound of formula (III) H-R 3 (III), wherein R 3 is as defined hereinbefore; and (ii) any protecting groups are removed and the resulting compound of formula (II) is recovered in its free form or that of a pharmaceutically acceptable salt.

The compound of formula (II) can be prepared by reacting a compound of formula (IV)

in which R 'is equivalent to Rla and Rlb; R 20 and U are equivalent to U 1 and a 2, and are as defined in claim 1; V is H or a protecting group; T is an leaving group, with a compound of formula H-A-V, wherein A is as defined hereinbefore; and V is H or a protecting group, to provide a compound of formula (VI)

, R / HN

VO 0V (VI)

Compound (VI) may be reacted with a compound of formula (VII)

V0 0V in which, (VII) ΡΕ2066669 18 R1 is equivalent to Rla and Rlb; U is equivalent to Ui and U2; V are as defined in claim 1; and T and T2 are halogen.

The compound of formula (VII) can be prepared by reacting a compound of formula (VIII)

(VIII) in which R 1 is equivalent to R 1a and R 1b; U is equivalent to Ui and U2; V are as defined in claim 1; and Q represents an acid salt or a protected derivative thereof with a 2,6-dihalopurine, for example 2,6-dichloropurine, to give a compound of formula (VII)

1 1 to 1 K R is equivalent to R and aR; U is equivalent to Ui and U2; V are as defined in claim 1; and T and T2 are halogen.

The compounds of formula (I) may be prepared, for example, using the reactions and techniques described below and in the Examples. The compounds of formula (I) can be prepared analogously to the preparations described in the applicant's patent applications PCT / EP 2005 / 011,344, GB 0 500,785.1, and GB 0 505,219.6. The reactions may be carried out in a solvent appropriate to the reagents and materials employed, and suitable for the transformations being carried out. Those skilled in the art of organic synthesis will appreciate that the functionality present in the molecule should be consistent with the proposed transformations. This will require some 20 to 2066669 cases to resort to opinions to alter the order of synthetic steps or to select a well-defined procedural scheme over another to obtain a desired compound of the invention.

The various substituents of the synthetic intermediates and end products shown in the following reaction schemes may be present in their fully developed forms, using protecting groups where this is required as is known to a person skilled in the art, or may take the form of its most burning precursors can be transformed into the final forms by methods which are known to one skilled in the art. The substituents may also be added at various times throughout the synthetic sequence or after completion of the synthetic sequence. In many cases, usual manipulations of functional groups may be used to transform an intermediate into another intermediate, or a compound of formula (I) into another compound of formula (I). Examples of such manipulations are the conversion of an ester or a ketone into an alcohol; the conversion of an ester into a ketone; the interconversions of esters, acids and amides; alkylation, acylation and sulfonylation of alcohols and amines; and many others. Substituents may also be added using standard reactions, such as alkylation, acylation, halogenation or oxidation. Such manipulations are well known in the art, and many reference works summarize processes and methods for such manipulations. Some of the reference works which contain examples and citations of the primary literature of organic synthesis for many functional group manipulations, as well as for other transformations commonly used in the art of organic synthesis, are: March, Organic Chemistry, 5th Edition, Wiley and Chichester, Editores (2001); Comprehen-sive Organic Transformations, Larock, Ed., VCH (1989); Comprehensive Organic Functional Group Transformations, by Katritzky et al. (series editors), Pergamon (1995); and Comprehensive Organic Synthesis, Trost and Fleming (series editors), Pergamon (1991). It is also well established that another primary fact to be taken into consideration when planning any route of synthesis in this domain is the judicious choice of the protecting group which is used for the protection of the functional groups present in the compounds described in this invention. Various protecting groups may be chosen from the same molecule so that each of these protecting groups can either be removed without removing the other protecting groups in that molecule or so that several protecting groups can be removed using the same reaction step, depending on the desired result. A reference work that describes many alternative to the trained chemist is Greene and Wuts, Protective Groups In Organic Synthesis, Wiley and Sons (1999). It is understood by those skilled in the art that only combinations of substituents which are chemically possible constitute embodiments of the present invention.

The free forms can be converted to compounds of formula (I) in their salt forms, and vice versa, in a conventional manner. The compounds may be obtained in free form or salts thereof as hydrates or solvates containing a solvent used for their crystallization. Compounds of formula (I) may be recovered from reaction mixtures, and purified in conventional manners. Isomers, such as stereoisomers, may be obtained in a conventional manner, for example by fractional crystallization or by asymmetric synthesis from correspondingly optically active, asymmetrically substituted raw materials.

The compounds of formula (I) and their pharmaceutically acceptable salts are useful as pharmaceuticals. In particular, they activate the A2a adenosine receptor, i.e., they act as A2a receptor agonists. Their A2a receptor agonist properties can be demonstrated using the method described by Murphree et al., Mol. Pharmacol., 61, 455-462, (2002).

The compounds of the Examples hereinafter have K 2 values less than 1.0 μ in the assay referred to above. For example, the compound of Example 1 has a K 2 value of 0.76 μ. Regarding their activation of the adenosine A2a receptor, the compounds of formula (I), in their free form or that of a pharmaceutically acceptable salt thereof, hereinafter referred to as 23A2066669 alternatively as " invention " are useful in the treatment of conditions responsive to activation of the A2a adenosine receptor, especially in inflammatory or allergic conditions. The treatment according to the invention may be symptomatic or prophylactic.

The agents of the invention are therefore useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in a decrease in tissue damage, airway inflammation, bronchial hyperreactivity, remodeling or disease progression. Included in the inflammatory or obstructive airway diseases and conditions to which the present invention is applicable, acute lung injury (ALI), adult acute respiratory failure syndrome (ARDS), chronic obstructive pulmonary disease, respiratory disease, or of the lungs (COPD, COAD or COLD), including chronic bronchitis or dyspnoea associated with it, emphysema, as well as exacerbation of airway hyperreactivity during therapy with other drugs, especially in therapies with other drugs inhaled. The invention is also applicable to the treatment of bronchitis of any type or origin, including, for example, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Other inflammatory or obstructive airways diseases to which the present invention may be applicable include pneumoconiosis (an inflammatory, usually occupational, disease of the lungs, often accompanied by chronic obstructive airway obstruction, acute and chronic, and caused by repeated inhalation of dust) of any type or source, including, for example, aluminous, anthracosis, asbestosis, calicosis, ptosis, siderosis, silicosis, tabacosis and bissinosis.

Other inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of any type or origin including both intrinsic (non-allergic) and extrinsic (allergic) asthma, mild asthma, moderate asthma, asthma severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection. Treatment of asthma should also be understood as including treatment of subjects, for example, less than 4 or 5 years of age, who exhibit symptoms of wheezing and are diagnosed or diagnosed as " wheezy children ", a category of patients characterized which is a strong concern of the medical profession and nowadays identified as incipient or early stage asthma. (For convenience this particular asthmatic condition is referred to as " wheezing child syndrome "). Prophylactic efficacy in the treatment of asthma is revealed by a lower frequency or severity of symptomatic attacks, for example, acute asthmatic attacks or bronchoconstriction, improved lung function or improved airway hyperreactivity. It may also manifest itself through a minor need for other symptomatic therapies, i.e. therapy designed to restrict or abort a symptomatic attack when it occurs, for example, anti-inflammatory drugs (eg, corticosteroids) or bronchodilators the The prophylactic benefits in asthma may in particular become apparent in subjects prone to " morning dipping " (decrease in blood pressure). 0 " morning dipping " is a well recognized asthmatic symptom observed in a substantial percentage of asthmatics and characterized by an asthma attack, for example, between 4 and 6 o'clock in the morning, i.e., at a time when normally the last administration of symptomatic asthma therapy occurred there is plenty of time.

With respect to their anti-inflammatory activity, in particular as regards the inhibition of eosinophil activation, the agents of the invention are also useful in the treatment of eosinophil related conditions, for example eosinophilia, in particular related respiratory pathologies with eosinophils (for example, involving a morbid infiltration of eosinophils into lung tissues) including hypereosinophilia in the way it affects the airways and / or lungs, as well as, for example, airway pathologies related to eosinophils as a consequence or concomitantly with Löffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) pneumonia, infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including 26 ΡΕ2066669 syndrome

Churg-Strauss), eosinophilic granuloma, and eosinophil-related pathologies that affect the airway caused by drug reactions.

The agents of the invention are also useful in the treatment of inflammatory or allergic skin conditions, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, acquired epidermolysis bullosa, and other inflammatory and allergic skin conditions.

The agents of the invention may also be used for the treatment of other diseases or conditions, in particular diseases or conditions which have an inflammatory component, for example in the treatment of diseases and conditions of the eye such as conjunctivitis, kerato and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory diseases in which autoimmune reactions are involved, or which have an autoimmune component or etiology, including autoimmune hematological diseases ( for example hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis , the syndrome of 27 ΡΕ2066669

Steven-Johnson syndrome, idiopathic celiac disease, autoimmune inflammatory bowel disease (eg, ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic penumonitis hypersensitivity, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), dry keratoconjunctivitis and vernal keratoconjunctivitis, pulmonary interstitial fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, eg, including idiopathic nephrotic syndrome or minimal alteration nephropathy).

In addition, the agents of the invention may also be used for the treatment of cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, inflammatory bowel syndrome, wound healing, diabetic nephropathy as described in WO 05 / 107,463, for to decrease inflammation in transplanted tissue as described in US 2005 / 182,018, of inflammatory diseases caused by pathogenic organisms as described in WO 03 / 086,408, and of cardiovascular conditions as described in WO 03 / 029,264.

The agents of the invention may also be used to ascertain the severity of coronary artery stenosis as described in WO 00 / 078,774, and are useful in conjunction with radioactive imaging agents to obtain images of coronary activity, and are useful in therapy attached with angioplasty, as described in WO 00/78779. ΡΕ2066669

The agents of the invention are also useful in conjunction with a protease inhibitor to prevent organ ischemia and reperfusion injury, as described in WO 05 / 003,150, and together with an integrin antagonist to treat platelet aggregation, such as described in WO 03/090733.

The agents of the invention are also useful for promoting wound healing in bronchial epithelial cells, as described in AJP-Lung, 290, 849-855.

Other diseases and conditions which may be treated with the agents of the invention include diabetes mellitus, type I diabetes mellitus (juvenile diabetes) and type II diabetes mellitus, diarrheal diseases, ischemia / reperfusion injury, retinopathy such as diabetic retinopathy or oxygen-induced hyperbaric retinopathy, conditions characterized by elevated intraocular tension or ocular aqueous humor secretion such as glaucoma, ischemic damage to tissues and organs from reperfusion, and bedridden wounds.

The effectiveness of an agent of the invention can be demonstrated in inhibiting inflammatory states, for example in inflammatory airway diseases, in an animal model, for example in a model of airway inflammation or other inflammatory conditions in mice or rats, for example, as described in US Pat. No. 2,066,669 to Szarka et al., J. Immunol. Methods, 202, 49-57 (1997); Renzi et al., Am. See, Respir. Dis., 148, 932-939 (1993); Tsuyuki et al., J. Clin. Invest., 86, 2924-2931 (1995);

Cernadas et al., Am. J. Respir. Cell Mol. Biol., 20, 1-8 (1999); and Fozard et al., Eur. J. Pharmacol., 438, 183-188 (2002).

The agents of the invention are also useful as co-therapeutic agents for use in combination with other pharmaceutical substances, such as anti-inflammatory, bronchodilator, antihistaminic or antitussive pharmaceutical substances, in particular in the treatment of obstructive or inflammatory conditions of the airways such as those mentioned hereinbefore, for example, as enhancers of the therapeutic activity of such drugs or as a means to decrease the indispensable dosages or potential side effects of such drugs. An agent of the invention may be mixed with the other pharmaceutical substance in a well-defined pharmaceutical composition, or it may be administered separately prior to, concurrently with or after the other pharmaceutical substance. The invention therefore includes a combination of an agent of the invention as hereinbefore described, with an anti-inflammatory, bronchodilatory, antihistaminic or antitussive pharmaceutical substance, the agent of the invention being referred to and the said pharmaceutical substance in the same pharmaceutical composition, or 30 ΡΕ 2066669 in different compositions.

Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, mometasone ciclesonide or furoate, or steroids described in WO 02/88167, WO 02 (Particularly those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99, and 12). 101), WO 03 / 35,668, WO 03 / 48,181, WO 03 / 622,59, WO 03 / 64,445, WO 03 / 72,592, WO 04 / 39,827 and WO 04 / 66,920; non-steroid glucocorticoid receptor agonists, such as those described in DE 10 261 874, WO 00/00531, WO 02/10133, WO 03/82.280, WO 03/82777, WO 03/86294, WO 03/104195, WO 03 WO 04/05229, WO 04/18429, WO 04/19935 and WO 04/26248; antagonists of LTB4, such as BIIL 284, CP-195543, DPC11870, LTB4 ethanolamide, LY 293111, LY 255283, CGS025019C, CP-195543, ONO-4057, SB 209247, SC -53228 and those described in US 5,451,700; LTD4 antagonists such as montelukast, pranlucaste, zafirlukast, cachet, SR2640, Wy-48.252, ICI 198,615, MK-571, LY-171883, Ro 24-5,913 and L-648,051; Inhibitors of PDE4, such as cilomilast (Ariflo® GlaxoSmithKline), Roflumilaste (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plow), Arofiline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SelCID (TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW WO 93/19750, WO 93/19751, WO 98/18766, WO 99/16766, WO 01/13953, WO 93/19750, WO 93 / 03 / 104,204, WO 03 / 104,205, WO 03 / 39,544, WO 04 / 000,814, WO 04 / 000,839, WO 04 / 005,258, WO 04 / 018,450, WO 04 / 018,451, WO 04 / 018,457, WO 04 / 018,465, WO 04 / 018,431, WO 04 / 018,449, WO 04 / 018,450, WO 04/018451, WO 04/018457, WO 04/018484, WO 04/019944, WO 04/019945, WO 04/045607 and WO 04/037805; adenosine A2B receptor antagonists, such as those described in WO 02 / 42,298; and beta-2 adrenoceptor agonists, such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and in particular, formoterol, carmoterol and their acceptable salts of (as free, salt or solvate forms) of formula (I) in WO 00/75114, which document is incorporated herein by reference, preferably compounds of the Examples thereof, in which In particular a compound of formula

and their pharmaceutically acceptable salts, as well as compounds (in their free or salt or solvate form) of formula (I) of WO 04/16601, and also compounds of EP 1,440,966, JP 05,025,045, WO 32 ΡΕ2066669

93 / 18,007, WO 99 / 64,035, US 2002 / 0055,651, the US

2005/0133. 417, US 2005 / 5,159, WO 01 / 42,193, WO 01 / 83,462, WO 02 / 66,422, WO 02 / 70,490, WO 02 / 76,933, WO 03 / 24,439, WO 03 / 42,160, No. WO 03/42164, WO 03 / 72,539, WO 03 / 91,204, WO 03 / 99,764, WO 04 / 16,578, WO 04 / 22,547, WO 04 / 32,921, WO 04 / 33,412, WO 04 / 37,768, WO 04/37773, WO 04/37807, WO 04/39762, WO 04/39766, WO 04/45618, WO 04/46883, WO 04/80964, EP 1,460. 064, WO 04 / 087,142, WO 04 / 089,892, EP 1,477,167, US 2004 / 0242,622, US 2004/0229. 904, WO 04 / 108,675, WO 04 / 108,676, WO 05 / 033,121, WO 05/040103, WO 05/044777, WO 05/05867, WO 05/066550, WO 05/06640, WO2007 / 07908, WO2007 / 018,461, WO2007 / 027,133, WO2006 / 051,373, WO2006 / 056,471, and WO2004 / 016601.

Suitable bronchodilator drugs include anticholinergic or antimuscarinic agents, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), as well as glycopyrrolate, but also those described in EP 424 021, US 3,714,357, US 5,171,744, US 2005 / 171,147, US 2005 / 182,091, WO 01/04148, WO 02/00652, WO 02/1 51841, WO 02 / WO 03/33895, WO 03/53966, WO 03 / 87,094, WO 04 / 018,422, WO 04/05285 and WO 05/07 '7,361.

Suitable anti-inflammatory drugs and bronchodilators include both beta-2 adrenoceptor antagonists and muscarinics, such as those described in U.S. 2004 / 0167,167, U.S. 2004 / 0242,622, U.S.A. 2005 / 182,092, WO 04 / 74,246 and WO 04 / 7,412.

Suitable antihistamines include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastin, astemizole, azelastine, ebastine, epinastine, mizolastine and terfenadine, as well as those described in JP 2004 / 107,299, WO 03 / 099,807 and WO 04 / 026,841.

Other useful combinations of agents of the invention with anti-inflammatory drugs are those with chemokine receptor antagonists, for example CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR- 7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, in particular CCR-5 antagonists such as the Schering-Plow antagonists SC-351125, SCH-55700 and SCH-D, Takeda antagonists, such as N - [[4 - [[[6,7-dihydro-2- (4-methylphenyl) -5 H -benzo-cyclohepten-8-yl] carbonyl] amino chloride ] -amide] (TAK-770), and the CCR-5 antagonists described in US 6,166,037 (especially in claims 18 and 19) ), WO 00/66558 (in particular in claim 8), WO 00/66559 (in particular in claim 9), WO 04 / 018,425 and WO 04 / 026,873. 34 ΡΕ2066669

As described above is a method for the treatment of a condition responsive to an A2a adenosine receptor activation, for example, an inflammatory or allergic condition, in particular an inflammatory or allergic airway disease, including administering in particular to a human subject in need thereof, a compound of formula (I) in free form or in the form of a pharmaceutically acceptable salt thereof. In another aspect the invention provides a compound of formula (I), in its free form or in the form of a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a condition responsive to an activation of the A2a adenosine receptor, in particular an inflammatory or obstructive airway disease.

The agents of the invention may be administered by any suitable route, for example orally, for example in the form of a tablet or a capsule; parenterally, e.g. intravenously; by inhalation, for example, in the treatment of an inflammatory or obstructive airway disease; by intranasal route, for example, in the treatment of allergic rhinitis; by topical route on the skin, for example, in the treatment of atopic dermatitis; or rectally, for example in the treatment of inflammatory bowel disease. 35 ΡΕ2066669

In a further aspect, the invention also provides a pharmaceutical composition comprising compounds of formula (I), in free form thereof or in the form of a pharmaceutically acceptable salt, optionally together with an acceptable diluent or carrier thereof from the pharmaceutical point of view. The composition may contain a co-therapeutic agent, such as an anti-inflammatory drug, a bronchodilator, an antihistamine or antitussive as described hereinbefore. Such compositions may be prepared using conventional diluents or excipients and techniques which are known in galenic art. Thus oral dosage forms include tablets and capsules. Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, for example, tampons. The inhalation compositions may include aerosols or other sprayable formulations, or be dry powder formulations.

When the composition includes an aerosol formulation, it preferably contains, for example, a hydrofluoroalkane (HFA) as the entraining fluid, such as HFA134a or HFA227, or a mixture thereof, and may contain one or more known cosolvents in the such as ethanol (up to 20% by weight), and / or one or more surfactants such as oleic acid or sorbitan trioleate, and / or one or more bulking agents, such as lactose. When the composition includes a dry powder formulation, it preferably contains, for example, 36 ΡΕ 2066669 compounds of formula (I) with a particle diameter of less than or equal to 10 microns, optionally together with a diluent or carrier, such as the lactose, with the desired particle size distribution, and a compound which helps to protect against deterioration of the performance of the product due to moisture, for example magnesium stearate. Where the composition includes a nebulized formulation, it preferably contains, for example, the compound of formula (I), either dissolved or suspended, in a vehicle containing water, a cosolvent, such as ethanol or propylene glycol, and a stabilizer, which may be a surfactant. The invention includes (A) a compound of formula (I) in an inhalable form, for example in an aerosol composition or other atomizable composition, or in the form of inhalable particles, for example in micronized form, (B) a inhalable medicament including a compound of formula (I) in inhalable form; (C) a pharmaceutical product comprising a compound of formula (I) in an inhalable form in association with an inhalation device; and (D) an inhalation device containing a compound of formula (I) in an inhalable form.

Dosages of the compounds of formula (I) which are employed in the practice of the present invention will of course depend, for example, on the specific state to be treated, the intended effect and the mode of administration. In general, the daily doses suitable for administration by inhalation are of the order of 0.005-10 mg, while for oral administration the appropriate daily doses are of the order of 0.05-100 mg. The invention is illustrated by the following Examples.

EXAMPLES

Compounds of formula X are shown in the following table. Methods for preparing compounds of these are described hereinafter.

Ex2 Structure Ri R 2 R 3 R 1 R 1 1 G 2 O 2 0 0 0 0 0 0 0 0 0 0 0 0 0 ΡΕ2066669 (cont'd) οι κ ω Structure Ri r2 r3 R4 Rs 2 OyO Jpòu, VO fcc ° yj Xr OyO ΗΛΓ 1 0% 3 OyO X " s-o-hCk, / Λ Xf OyO T £ OH, X < aL 5 OyO Hf <r αχ "Λ-« iS. (O) -O-O-O-O-O-O-O-O-O-O-O-O-O-O-O-O. -1¾ 39 ΡΕ2066669 (cont'd)

01 X ω Structure Ri R 2 R 3 R 4 R 7 Mo * OH 'Xx. ÒCyX &quot; X OyO T -ClX &quot; U H 8 O & O HO. hc &gt; - * v ςν OyO HK X \ NH

Preparation of intermediates

The abbreviations used are as follows: HCl Hydrochloric acid LCMS Liquid Chromatography Mass Spectroscopy MeOH Methanol NMP n-Methylpyrrolidone NMO N-Methylmorpholine N-oxide TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran CDI 1,1'-Carbonyldiimidazole DCM Dichloromethane DEAD Diethyl Azodicarboxylate DIPEA Di-isopropylethylamine DMF Dimethylformamide DMSO Dimethyl Sulfoxide EDC1 1-Ethyl-3- (3'-dimethylamino-propyl) -carbodiimide EtOAc Ethyl Acetate HPLC High Performance Liquid Chromatography 40 ΡΕ2066669

Table 1 below lists the following intermediates of formula (A)

as well as the method for the preparation thereof which is described hereinafter. TABLE 1

Intermediate Q M / s MH + AA cyo 521 AB O &quot; 475 AC 553

Intermediate AA N- {(1S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3- cyclopentyl] -propionamide

Step AAl (1S, 4A) -4- (2,6-Dichloro-purin-9-yl) -cyclopent-2-enol 41 ΡΕ2066669

2-β-Dichloropurine (10 g, 52.90 mmol), (1S, 4R) cis-4-acetoxy-2-cyclopenten-1-ol (10 g, 70.40 mmol), dibenzylideneacetone) dipalladium (0) (3.20 g, 3.50 mmol) and triphenylphosphine on polymeric support (at 3 mmol / g, 11.60 g, 35.00 mmol) in a pre-dried flask in an oven under an atmosphere of argon. Dry deoxygenated THF (80 mL) is added and the reaction is stirred gently for 5 minutes. TEA (20 mL) is added and the reaction mixture is stirred at 50 ° C. After 1 hour, the reaction was complete by LCMS. The reaction mixture is allowed to cool, filtered and the solvent is removed in vacuo. The titled compound is obtained after purification by flash column chromatography (silica, DCM / MeOH 25: 1). ¹H-NMR (CDCl,, 400 MHz); (M, 1H), 5 silica (m, 1H), 4 silica, 95 (m, 1H), 3 silica (m, 1H), 2 silica (m, 1H). MS (ES +) m / e 271 (MH +).

Step AA2: (1S, 4R) -4- (2,6-Dichloro-purin-9-yl) -cyclopent-2-enyl ester Carbonic acid ethyl ester

(1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enol (9.5 g, 35.05 mmol) is placed in a pre-dried flask in an oven, under an argon atmosphere. Dry THF (200 mL) is added, followed by dry pyridine (5.54 g, 70.1 mmol). Ethyl chloroformate (15.21 42 Å and 2066669 g, 140.2 mmol) is slowly added so that the temperature does not exceed 40øC and the reaction mixture is stirred at room temperature. After 1 hour an LCMS shows that the reaction is complete. The solvent is removed in vacuo and the residue taken up in DCM (200 mL) and water (200 mL). The organic phase is washed with water (150 mL) and brine (150 mL), dried over MgSO4, filtered and the solvent is removed in vacuo. The title compound is obtained after crystallization from MeOH. 1 H NMR (CDCl 3, 400 MHz); (M, 1H), 5.75 (m, 1H), 5.70 (m, 1H), 4.25 (m, 1H) , 2H), 3.20 (m, 1H), 2.05 (m, 1H), 1.35 (t, 3H). MS (ES +) m / e 343 (MH +).

Step AA3: Di-Boc - [(1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl] -amine

(IS, 4R) -4- (2,6-Dichloro-purin-9-yl) -cyclopent-2-enyl ester, carbonic acid ethyl ester, is placed in a pre-dried flask in an oven, under an argon atmosphere (2.5 g, 7.29 mmol), di-t-butyl iminodicarboxylate (1.74 g, 8.02 mmol), and triphenylphosphine (0.29 g, 1.09 mmol). Deoxygenated dry THF (30 ml) and then tris (dibenzylideneacetone) dipalladium (0) (0.33 g, 0.36 mmol) are added and the reaction mixture is stirred at room temperature. After 3 hours, LCMS demonstrates that the reaction is complete. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica, EtOAc / isohexane 4: 1). NMR (CDCl3, 400 MHz); 8.70 (s, 1H), 6.20 (m, 1H), 5.85 (m, 1H), 5.80 (m, 1H), 5.40 (m, 1H), 3.20 (m , 1H), 2.15 (m, 1H), 1.55 (s, 18H). MS (ES +) m / e 470 (MH +).

Step AA4: (1S, 2R, 3S, 5R) -3- (Di-Boc-amino) -5- (2,6-dichloro-purin-9-yl) -cyclopentane-1,2-diol

A mixture of di-Boc - [(1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl] -amine (1.30 g, 77 mmol) (1.49 g, 3.17 mmol), methanesulfonamide (0.30 g, 3.17 mmol) and AD-mix-a (6.75 g, 1.5 g / mmol) in t-butanol / water (20 mL of a 1: 1 mixture) was treated with osmium tetroxide (1.5 mL, 4% by weight, in water). After stirring vigorously at room temperature overnight, the reaction mixture is partitioned between ethyl acetate and water. Separate the organic phase, wash with water, brine, dry (MgSO4) and concentrate in vacuo to give the title compound which is used in the next step without further purification. 1 H-NMR (CDCl3, 400 MHz); 8.35 (s, 1H), 4.80 (m, 1H), 4.70 (m, 1H), 4.50 (m, 1H), 3.85 (m, 1H), 3.75 (m (M, 1H), 2.75 (m, 1H), 2.55 (m, 1H), 1.55 (s, 18H). MS (ES +) m / e 504 (MH +). 44 ΡΕ2066669

Step AA5: (1S, 2R, 3S, 5R) -3-Amino-5- (2,6-dichloro-purin-9-yl) -cyclopentane-1,2-diol trifluoroacetate

A solution of (1S, 2R, 3S, 5R) -3- (di-boc-amino) -5- (2,6-dichloro-purin-9-yl) -cyclopentane-1,2-diol ( 0.55 g, 1.09 mmol) in DCM (4 mL) was treated with TFA (2 mL) and stirred at room temperature. After 2 hours, the solvent is removed in vacuo to give the title compound which is used in the next step without further purification. MS (ES +) m / e 304 (MH +).

Step AA6: N - [(1S, 2R, 3S, 4R) -4- (2,6-Dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide

A solution of (1S, 2R, 3S, 5R) -3-amino-5- (2,6-dichloro-purin-9-yl) -cyclopentane-1,2-diol trifluoroacetate (0.304 g , 1.0 mmol) in THF (10 mL) was treated with DlPEA (0.387 g, 3.0 mmol) and then with propionyl chloride (0.093 g, 1.0 mmol). After stirring at room temperature for 2 hours, the solvent is removed in vacuo and the title compound is obtained after purification by reverse phase chromatography (Isolute ™ C18, 0-100% acetonitrile in water, 1% TFA). MS (ES +) m / e 360 (MH +).

Step AA7: N - {(1S, 2R, 3S, AR) -4- [2-Chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3- cyclopentyl} -propionamide 45 ΡΕ2066669

N - [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-pyridin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide (160 mg, 0.44 mmol) in THF (5 mL) under an atmosphere of argon. DIPEA (69 mg, 0.53 mmol) and then 2,2-diphenylethylamine (96 mg, 0.49 mmol) are added and the reaction mixture is stirred at 50 ° C. After 2 hours, LCMS shows that the reaction is complete. The solvent is removed in vacuo and the titled compound is obtained after purification by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% TFA).  € ƒâ € ƒâ € ƒ1 H NMR (MeOD, 400 MHz): Î'0.90 (s, 1H), 7.17 (m, 10H), 4.75 (m, 1H), 4.60 (m, 1H), 4.50 (m, (m, 1H), 4.20 (m, 1H), 2.85 (m, 1H), 2.40 (q, 2H), 2.10 (m, 1H), 1.20 (t, 3H) MS (ES +) m / e 521 (MH +).

Intermediate AA can also be prepared using the following procedure:

Step AA / 1: (2-Chloro-9 - [(1S, 4S) -4- (di-boc-amino) -cyclopent-2-enyl] -9H-purin-6-yl} - (2,2- diphenyl-ethyl) -amine

Dissolve (1S, 2R, 3S, 5R) -3- (di-boc-amino) -5- (2,6-dichloro-purin-9-yl) -cyclopentane-1,2-diol (13.0 , 27.66 mmol) in THF (250 mL) under an argon atmosphere. DIPEA (4.28 g, 33.19 mmol) and then 2,2-diphenylethylamine (6.0 g, 30.43 mmol) are added and the reaction is stirred at 50 ° C. After 18 hours, LCMS shows that the reaction is complete. The solvent is removed in vacuo and the reaction mixture is partitioned between dichloromethane (250 mL) and 0.1 M HCl (250 mL). The organic phase is washed with water (200 ml) and brine (200 ml), dried over

MgSO 4, filter and remove the solvent in vacuo to give the title compound. NMR (CDCl3, 400 MHz); 8.05 (s, 1H), 7.30-7.10 (m, 10H), 6.00 (m, 1H), 5.70 (m, 2H), 5.60 (m, (M, 1H), 3.65 (m, 1H), 3.05 (m, 1H), 2.00 (m, 1H) 1H), 1.70 (m, 1H), 1.40 (s, 18H). MS (ES +) m / e 631 (MH +).

(1R, 2S, 3R, 5S) -3- [2-Chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -5- (di-boc-amino) -cyclopentane-1,2-diol

The title compound is prepared in a manner analogous to (1S, 2R, 3S, 5R) -3- (di-boc-amino) -5- (2,6-dichloro-purin-9-yl) -cyclopentane- 1,2-diol replacing di-Boc - [(1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl] -amine for {2-chloro-9- [(1R, 4S) -4- (di-boc-amino) -cyclopent-2-enyl] -9 H -purin-6-yl} - (2,2-diphenyl-ethyl) -amine. NMR (MeOD, 400 MHz); 8.05 (s, 1H), 7.35-7.15 (m, 10H), 4.70-4.55 (m, 4H), 4.50 (m, 1H), 4.35 (m, 1H), 4.20 (m, 2H), 2.55 (m, 1H), 2.45 (m, 1H), 1.60 (s, 18H). 47 ΡΕ2066669

Step AA / 3: (1Sr2R, 3S, 5R) -3-Amino-5- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -cyclopentane-1,2-trifluoroacetate diol

Dissolve (1R, 2S, 3R, 5S) -3- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -5- (di-boc-amino) -cyclopentane -1,2-diol (10.3 g, 15.50 mmol) in DCM (50 mL). TFA (25 mL) is added and the reaction mixture is stirred at room temperature. After 2 hours, LCMS shows that the reaction is complete. The solvent is removed in vacuo to give the title compound. NMR (MeOD, 400 MHz): 7.90 (s, 1H), 7.30-7.10 (m, 10H), 4.65 (m, 1H), 4.50 (m, (M, 1H), 2.40 (m, 1H), 4.20 (m, 1H) 1H). MS (ES +) m / e 465 (MH +).

Step AA / 4: N - {(1S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-di -hydroxy-cyclopentyl} -propionamide

TFA of (1S, 2R, 3S, 5R) -3-amino-5- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -cyclopentane-1,2 (9.50 g, 16.42 mmol) and DIPEA (6.36 g, 49.27 mmol) in a flask was treated with dry THF (150 mL). Propionyl chloride (1.52 g, 16.42 mmol) is added dropwise and the reaction mixture is stirred at room temperature. After 1 hour an LCMS shows that the reaction is complete. The solvent is removed in vacuo and the residue is taken up in DCM (250 mL) and 48 ΡΕ 2066669 water (250 mL). The organic phase is washed with water (200 mL) and brine (200 mL), dried over MgSO4, filtered and the solvent is removed in vacuo. The solid is recrystallized from 1,2-dichloroethane to give the title compound. 1 H-NMR (MeOD, 400 MHz); 8.00 (s, 1H), 7.15 (m, 10H), 4.75 (m, 1H), 4.60 (m, 1H), 4.50 (m, 1H), 4.20 (m, 3H), 3.95 (m, 1H), 2.85 (m, 1H), 2.40 (q, 2H), 2.10 (m, 1H) . MS (ES +) m / e 521 (MH +).

Intermediate AB

N - {(1S, 2R, 3S, 4R) -4- [2-Chloro-6 - ((S) -1-hydroxymethyl-2-phenyl-ethylamino) -purin- 3-dihydroxy-cyclopentyl} -propionamide

Step ABI: [(15,4Λ) -4- (2,6-Dichloro-purin-9-yl) -cyclopent-2-enyl] -propionyl-carbamic acid tert-butyl ester

The title compound is prepared analogously to di-boc - [(1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl] -amine (substituting the iminodicarboxylate of di-t-butyl by propionyl-carbamic acid tert-butyl ester.

Step AB2: [(1S, 2R, 3S, 4R) -4- (2,6-Dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionyl- carbamate 49 ΡΕ2066669

A mixture containing [(1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl] -propionyl-carbamic acid tert- And AD-mix-a (23 g, 1.5 g / mmol) in t-butanol / water (80 mL of a 1: 1 mixture) with osmium tetroxide (3.5 mL, 4% by weight, in water). After stirring vigorously at room temperature for 72 hours, the reaction mixture is partitioned between EtOAc and water. Separate the organic phase, wash with water, brine, dry (MgSO4) and concentrate in vacuo. The resulting residue is triturated with methanol to give the title compound. MS (ES +) m / e 460 (MH +).

Step AB3: N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6 - ((S) -1-hydroxymethyl-2-phenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide

A solution containing [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] (S) -2-amino-3-phenyl-propan-1-ol (0.181 mg, 1.0 mmol) 2 mmol) in 1,2-dichloroethane (3 mL) at 50 ° C overnight. 0.1 M HCl (10 mL) is added and after stirring the reaction mixture, the organic phase is separated and treated with TFA (1 mL). After allowing to stand at room temperature for 2 hours, the solvent is removed in vacuo to give the title compound. MS (ES +) m / e 475.2 (MH +). ΡΕ2066669 50

Intermediate AC

This compound is prepared analogously to Intermediate AB, substituting 4,4 '- (2-aminoethylidene) bisphenol for the (S) -2-amino-3-phenyl-propan-1-ol (prepared according to preparation of Schelkun et al., Bioorg. Med. Chem. Lett., 9, 2447-2452 (1999) MS (ES +) m / e 553.2 (MH +).

Intermediate B

N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin- 9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide

Step B: (R) -1- [9 - ((1 S, 2 S, 3 R, 4 S) -2,3-Dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2- diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic acid tert-butyl ester

A reaction mixture containing N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3- dihydroxy-cyclopentyl} -propionamide (2.5 g, 4.80 mmol) and (3R) - (+) - (3-boc-amino) pyrrolidine (2.5 g, 13.6 mmol) in DMSO ( 8 mL) at 100 ° C overnight. Purification of the product by reverse phase column chromatography (Isolute ™ C18, 0-20% acetonitrile in 0.1% TFA water) affords the title compound. MS (ES +) m / e 521.4 (MH +). 51 ΡΕ2066669

Step B2: N - {(1S, 2R, 35R) -4- [2 - ((R) -3-Amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide:

{(R) -1- [9 - ((1R, 2S, 3R, 45) -2,3-Dihydroxy-4-propionylamino-cyclopentyl) -6- (2,4- 2-yl] -pyrrolidin-3-yl} -carbamic acid tert-butyl ester (about 4.80 mmol) in 1.25 M HCl in MeOH (60 mL). After stirring at room temperature for 3 days, the solvent was removed in vacuo to give the title compound. MS (ES +) m / e 571.24 (MH +).

Intermediate C N - {(1S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl } -2-hydroxy-acetamide

Step C1: {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentylcarbamoyl ester } -methyl ester

A suspension of (1S, 2R, 3S, 5R) -3-amino-5- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -cyclopentane- 1,2-diol (Intermediate AAI3) (250 mg, 0.46 mmol) in dry THF (10 mL) was treated with TEA (0.188 g, 1.86 mmol) and then acetoxyacetyl chloride (0.064 g, 46 mmol), and then stirred at room temperature 52 Å 2066669 for 30 minutes. The solvent is removed in vacuo and the residue is taken up in DCM and 0.1 M HCl. The organic phase is separated and washed with brine, dried (MgSO4) and concentrated in vacuo to give the title product. MS (ES +) m / e 565.38 (MH +).

Step C2: N - {(1S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3- cyclopentyl} -2-hydroxy-acetamide.

To a suspension of (1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3- dihydroxy-cyclopentylcarbamoyl} -methyl ester (0.2 g, 0.35 mmol) in MeOH (10 mL), potassium carbonate (0.098 g, 0.7 mmol) was added and the reaction mixture at room temperature for 1 hour. The solvent is removed in vacuo and the residue taken up in DCM and water. Separate the organic phase, dry (MgSO4) and concentrate in vacuo to give the title product. MS (ES +) m / e 522.4 / 524.5 (MH +).

Intermediate D (1 - [(1S, 4R) -4- (2,6-Dichloro-purin-9-yl) -cyclopent-2-enyl] -1H-pyrazol-4-yl} -methanol

A mixture of (1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enylic acid ethyl ester of carbonic acid (Intermediate AA2) (1.00 g, (0.49 g, 3.50 mmol) and triphenylphosphine (0.115 g, 0.44 mmol) in deoxygenated THF (10 mL) under an inert atmosphere of argon was treated with tris (dibenzylideneacetone) dipalladium (0) (0.13 g, 0.15 mmol) and stirred at 50 ° C for 1 hour. Remove the solvent in vacuo and purify the crude product by silica chromatography eluting with MeOH / DCM (1:25) to give the title compound.

Preparation of (1H-pyrazol-4-yl) -methanol

4-Ethyl pyrazole carboxylate (10 g, 71.40 mmol) is placed in a pre-dried flask in an oven under an argon atmosphere. Dry THF (100 mL) and then, dropwise, lithium aluminum hydride (1M in THF, 100 mL, 100 mmol) are added. After the addition is complete, the reaction mixture is stirred at 50 ° C. After 4 hours, LCMS shows that the reaction is complete. The reaction mixture is cooled in an ice bath and water (3.8 mL) is added to the reaction mixture to terminate the reaction, and then a 15% sodium hydroxide solution (3.8 mL), and again water (11.4 mL). The solvent is removed in vacuo and the solid is placed in a Soxhlet apparatus. THF is refluxed through the system for 24 hours. The solvent is removed in vacuo to give the title compound. 1 H-NMR (MeOD, 400 MHz); 7.60 (s, 2H), 4.55 (s, 2H). ΡΕ2066669 54

Intermediate E [4 - ((R) -3-pyrrolidin-3-ylureido) -cyclohexyl] -carbamic acid tert-butyl ester

Step E: (4-tert-Butoxycarbonylamino-cyclohexyl) -carbamic acid phenyl ester

Phenyl chloroformate (1 eq.) Is added dropwise to a solution of pyridine / DCM. The reaction mixture is cooled to 0 ° C and a solution of (4-amino-cyclohexyl) -carbamic acid tert-butyl ester (1eq) in DCM is added dropwise. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is partitioned between HCl (aq) (0.2 M) and DCM. the organic phase is washed with water, saturated sodium hydrogen carbonate solution and brine. The combined organic phases are dried (MgSO4), filtered and concentrated in vacuo to give the title compound.

Step E2: {4- [3 - ((R) -1-Benzyl-pyrrolidin-3-yl) -ureido] -cyclohexyl} -carbamic acid tert-

A solution of (4-tert-butoxycarbonylamino-cyclohexyl) -carbamic acid phenyl ester (1eq.) And (R) -1-benzyl-pyrrolidin-3-ylamine (1eq.) In MeOH using microwave radiation at 100 ° C for 30 minutes. The resulting solution is purified by reversed-phase column chromatography (Isolute ™ C18, 0-100% 55 ΡΕ2066669 trilus in water - 0.1% HCl) to provide the title compound.

Step E3: [4 - ((R) -3-pyrrolidin-3-ylureido) -cyclohexyl] -carbamic acid tert-butyl ester

To a solution of {4- [3 - ((R) -1-benzyl-pyrrolidin-3-yl) -ureido] -cyclohexyl} -carbamic acid tert-butyl ester in ethanol under an atmosphere inert gas of argon, palladium hydroxide on carbon. Purge the reaction mixture with argon and place under an atmosphere of hydrogen overnight. The mixture is filtered and the catalyst is washed with ethanol. The organic phases are combined and concentrated in vacuo to give the title compound.

Intermediate F [(R) -1 - ((R) -pyrrolidin-3-ylcarbamoyl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester

This compound is prepared analogously to Intermediate E, substituting (4-aminocyclohexyl) -carbamic acid tert-butyl ester for (R) -pyrrolidin-3-yl-carbamic acid tert-butyl ester.

Intermediate F

[(R) -1 - ((R) -pyrrolidin-3-ylcarbamoyl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester can be prepared using the following procedure

Step F1: ((R) -1-Benzyl-pyrrolidin-3-yl) -carbamic acid 4-nitrophenyl ester

4-Nitrophenyl chloroformate (1 eq.) Is added dropwise to a pyridine / DCM solution (1: 5) at 0 ° C. The reaction mixture is maintained at 0 ° C and a solution of (R) -1-benzyl-pyrrolidin-3-ylamine (1eq) in DCM is added dropwise. The reaction mixture is stirred at room temperature overnight. The reaction mixture is partitioned between HCl (aq) (0.2 M) and DCM. The combined organic phases are washed with a saturated aqueous solution of sodium hydrogen carbonate and brine. The combined organic phases are dried (MgSO4), filtered and concentrated in vacuo to give the title compound. MS (ES +) m / e 342.10 (MH +).

Step F2: [(R) -1 - ((R) -1-benzyl-pyrrolidin-3-ylcarbamoyl) -pyrrolidin-3-yl] -carbamic acid tert-

A solution of ((R) -1-benzyl-pyrrolidin-3-yl) -carbamic acid 4-nitro-phenyl ester (1eq) and (3R) - (+) - 3- (Boc- amino) pyrrolidine in MeOH using microwave radiation at 100 ° C for 1 hour. The reaction mixture is concentrated in vacuo. The resulting oil is dissolved in DCM and isocyanate resin (357 E 2066669 eq.) Is added and the mixture is stirred overnight. The resin was collected by filtration and the DCM was removed in vacuo to give the title compound. MS (ES +) m / e 299.21 (MH +).

Step F3: [(R) -1 - ((R) -pyrrolidin-3-ylcarbamoyl) -pyrrolidin-3-yl] -carbamic acid tert-

Add to a solution of [(R) -1 - ((R) -1-benzyl-pyrrolidin-3-ylcarbamoyl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester in an inert atmosphere of argon, palladium on carbon hydroxide. The reaction mixture is purged with nitrogen and placed under an atmosphere of hydrogen overnight. The mixture is filtered and the catalyst is washed with ethanol. The organic phases are mixed and concentrated in vacuo. The resulting brown oil is purified by column chromatography (Isolute ™ Si, 2% MeOH in DCM) to give the title compound. MS (ES +) m / e 389.25 (MH +).

Intermediate G {4- [3- (4-Amino-cyclohexyl) -ureido] -cyclohexyl} -carbamic acid tert-butyl ester

This compound is prepared analogously to Intermediate E substituting (R) -1-benzyl-pyrrolidin-3-ylamine (Step E2) for (4-amino-cyclohexyl) -carbamic acid benzyl ester. ΡΕ2066669 58

Intermediate [[1 - ((R) -pyrrolidin-3-ylcarbamoyl) -piperidin-4-yl] -carbamic acid tert-butyl ester

This compound is prepared analogously to Intermediate F substituting (3 R) - (+) - 3- (Boc-amino) pyrrolidine for piperidin-4-yl-carbamic acid tert-butyl ester in step F2.

Intermediate I {4- [4- (pyrrolidin-3-ylamino) - [1,3,5] triazin-2-ylamino] -cyclohexyl} -carbamic acid tert-butyl ester

Step 1: (R) -3- [4- (4-tert-butoxycarbonylamino-cyclohexylamino) - [1,3,5] triazin-2-ylamino] -pyrrolidine-1-carboxylic acid allyl ester

(R) -3-Amino-pyrrolidine-1-carboxylic acid allyl ester (1eq.) Is dissolved in DCM. The reaction mixture is cooled to 0 ° C and a solution of 2,4-dichloro- [1,3,5] triazine (1eq) in DCM is added dropwise. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is cooled to 0 ° C and a solution of (4-amino-cyclohexyl) -carbamic acid tert-butyl ester (1eq) in DCM is added dropwise. The reaction mixture is stirred at room temperature overnight. The reaction mixture is taken up in HCl (aq) (0.2 M) and DCM. The organic phase is washed with water, saturated NaHCO 3 solution (aq) and brine. The combined organic phases are dried (MgSO4), filtered and concentrated in vacuo to give the title compound.

Step 2: {4- [4 - ((R) -pyrrolidin-3-ylamino) - [1,3,5] triazin-2-ylamino] -cyclohexyl} -carbamic acid tert-butyl ester

It can be manufactured from the product of Step 1 according to the reference: Forns et al., Tetrahedron Lett., 44 (36), 6907-6910 (2003). Using (R) -3- [4- (4-tert-butoxycarbonylamino-cyclohexylamino) - [1,3,5] triazin-2-ylamino] -pyrrolidine-1-carboxylic acid allyl ester instead the amine bound to the resin.

Preparation of Examples

Example 1 N - {(1S, 2R, 35,4R) -4- [2 - {(R) -3- [2-Chloro-9 - ((1R, 2,5,3R, 4S) -2,3-di 4-propionylamino-cyclopentyl) -9H-purin-6-ylamino] -pyrrolidin-1-yl} -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3- dihydroxy-cyclopentyl} -propionamide

Step 1: [(1S, 2R, 35, 4R) -4- (2-chloro-6 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) - 2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-ylamino} -purin-9-yl) - 2,3-dihydroxy-cyclopentyl] -di-carbamic acid tert-butyl ester 60 ΡΕ2066669

(1S, 2R, 3S, 5R) -3- (di-Boc-amino) -5- (2,6-dichloro-purin-9-yl) -cyclopentane-1,2-diol (Intermediate AA4) (2R, 3R) -3-amino-pyrrolidin-1-yl) -6- (2,2,2-trifluoroethyl) 2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (Intermediate B) (58 mg, 0.10 mmol) in 1-PrOH (1 mL). Add DIPEA (0.089 mL, 0.51 mmol) and heat the reaction mixture using microwave radiation at 100 ° C for 1 hour. The reaction mixture is partitioned between water and the organic phase is dried (MgSO4), filtered and concentrated in vacuo. Purification by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water) affords the title compound. (MH + 1038/1040).

Step 2: N - {(1S, 2R, 3S, 4R) -4- [2 - {(R) -3- [9 - ((1R, 2S, 3R, 4S) -4- 2,3-dihydroxy-cyclopentyl) -2-chloro-9 H -purin-6-ylamino] -pyrrolidin-1-yl} -6- (2,2-diphenyl-ethylamino) -purin-9-yl] - 2,3-dihydroxy-cyclopentyl} -propionamide

[(1S, 2R, 3S, 4R) -4- (2-chloro-6 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) - 2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-ylamino} -purin-9-yl) - 2,3-dihydroxy-cyclopentyl] -di-carbamic acid benzyl ester (39 mg, 0.038 mmol) in MeOH (1 mL) and HCl (4M) in dioxane (1 mL) was added. The reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo to give the title compound. (MH + 838).

Step 3: N - {(1S, 2R, 3S, 4R) -4- [2 - {(R) -3- [2-Chloro-9 - ((1R, 2S, 3R, 4S) -2,3- dihydroxy-4-propionylamino-cyclopentyl) -9 H -purin-6-ylamino] -pyrrolidin-1-yl} -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3- dihydroxy-cyclopentyl} -propionamide

N - {(1S, 2R, 3S, 4R) -4- [2 - {(R) -3- [9 - ((1R, 2S, 3R, 4S) -4-Amino-2- , 3-dihydroxy-cyclopentyl) -2-chloro-9-purin-6-ylamino] -pyrrolidin-1-yl} -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2- , 3-dihydroxy-cyclopentyl} -propionamide (32 mg, 0.038 mmol) and TEA (0.016 mL, 0.113 mmol) in THF (0.5 mL) is added MeOH (0.5 mL) to aid dissolution . Propionic acid chloride (0.0035 mL, 0.040 mmol) is added and the reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and purified by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% TFA) to give the title compound (MH + 894 / 895).

Example 2 N - {(1S, 2R, 3S, 4R) -4- [2 - {(R) -3- [2 - [(R) -3- (3-Pyridin-3-yl-ureido) pyrrolidin-1-yl] -9- ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-6-ylamino] -pyrrolidin-1-yl} -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide 62 ΡΕ2066669

N - {(1S, 2R, 3S, 4R) -4- [2 - {(R) -3- [2-chloro-9 - ((1R, 2S, 3R, 4S) Dihydroxy-4-propionylamino-cyclopentyl) -9β-purin-6-ylamino] -pyrrolidin-1-yl} -6- (2,2-diphenyl-ethylamino) -purin-9- (1eq.) And 1-pyridin-3-yl-3- (R) -pyrrolidin-3-yl-urea (3eq.) In EtOH. The reaction mixture is refluxed at ambient temperature for 48 hours. The reaction mixture is concentrated in vacuo and purified by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% TFA) to provide the title compound.

Examples 3 are prepared individually by the following methods which are described for multi-parallel synthesis.

The Examples of the formula (I) are prepared in a multiparallel reaction sequence as described below.

ΡΕ2066669 - 63 -

Scheme 1 -

Af.

&lt; A-S-SS &lt; / RTI &gt; Ϊ Ϊ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ ΎΥΒ

ΠAAA AS AS AS AS j j j j j j j j j j j tiv tiv tiv tiv tiv tiv tiv tiv tiv tiv tiv tiv tiv tiv tiv tiv tiv tiv tiv tiv tiv tiv tiv j j tiv tiv j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j j

The invention relates to a process for the preparation of a compound of formula (I) in which the compound of the formula (I) is selected from the group consisting of CSM and isomers. Vampire; '&quot; &quot; . : '&gt; xrj &quot;. ' xxxx \ x \ xvw. \ w.w.w.v4k EfitSStt & &lt; 1 &gt; 4 &lt; / RTI &gt; Y.SX 0 *

U. ν · ϊΛ ϊΛ W N N · N N 1--8

tV * Ή &gt; v * W t> & Stsc

rvsjiji

V-5 * ··························································

Step 1:

Reaction of Intermediate AA3 in a manner analogous to that used in the preparation of Intermediate ΆΆΙ 1, substituting the appropriate amine for each of the Y-H amines, replacing the diphenylethylamine with Intermediate Y. ΡΕ2066669

Amines Y-H

Step 2:

Reaction of Intermediates Y individually with both the dihydroxylating reagent osmium tetroxide and ruthenium tetroxide yields Intermediates YA.

Step 3:

Reaction of Intermediates YA in a manner analogous to that used in the preparation of Intermediate AAI3 yields Intermediates YB.

Step 4:

Reaction of Intermediates YB with the appropriate acid chloride in a manner analogous to that used in the preparation of either Intermediate AAI4 (with propionyl chloride) or Intermediate C (with acetoxyacetyl chloride) gave Intermediates YX. ΡΕ2066669 65

YX Intermediates

Where Xa = CH3 CH2 C (O) -, CH30 C (O) -, H0 CH2 C (O) -, H0 CH (CH3) C (O) -

Step 5:

Reaction of Intermediates YX with (3R) - (+) - (3-boc-amino) pyrrolidine followed by deprotection in a manner analogous to that used in the preparation of Intermediate B yields YXA Intermediates.

Steps 6 and 7:

By reaction of the YXA, in a manner analogous to that used to prepare Example 1, using the appropriate acid chlorides of Step 3 individually, Intermediates YXC are obtained.

YXC Intermediates

Where Xb = CH3 CH2 C (O) -, CH30 C (O) -, HOCCH2 C (O) -, HOCH (CH3) C (O) -

Step 8:

Intermediates YXC are reacted in refluxing ethanol or in DMSO at 90-110øC for 18-24 hours, ΡΕ 2066669, preferably with a 3-fold excess of the appropriate Intermediate Z. The examples of Formula (I) are isolated after purification by mass directed reverse phase chromatography.

Intermediate Z

Where Z 21

NH, O / O 23

OH

The Examples of formula (II) may be prepared as described below in Scheme 2:

ΡΕ2066669 67

Scheme 2 Ολ 'P & sso 1 X / ΊΓ! 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, Xâ,, â, € â, € â, € â, € â,,â, (M + H) +. and VrtUfot

W &quot; £ H X2: 5

Pa: v, / + yxxi 5 / (i j / '&quot; ty

Π Π Π Π Π Π SM SM SM SM SM SM SM SM SM SM SM SM SM SM

IntBxmedia * Z *) * VrN, * - «Λ. &gt; -rV *% cv &gt; - + "" "" "" "" "" "" "-

Step S (A): A): [Image Omitted]

Step 1:

Reaction of Intermediate AA2 in a manner analogous to that used in the preparation of Intermediate D, replacing (1H-pyrazol-4-yl) -methanol by the appropriate heterocycle, individually with the heterocycles Xc-H, are obtained the Intermediates X2.

Heterocycles Xc-H

HO

HO ·

vV X3 ΡΕ2066669

The X-H heterocycles are prepared as follows: The preparation is described as that of Intermediate D. X 2 -X 3 are prepared following literature procedures.

Step 2:

Reaction of Intermediates X2, either with the dihydroxylating agent osmium tetroxide or with ruthenium tetroxide, yields Intermediates X2A.

Step 3:

Reaction of Intermediates X2A in a manner analogous to that used in the preparation of Intermediate AB, Step AB3, and substituting the appropriate amine with (S) -2-amino-3-phenyl-propan-1-ol amines YH, Intermediate X2Y is obtained.

Step 4:

Intermediates X2Y are reacted with (3R) - (+) - (3-boc-amino) pyrrolidine, followed by deprotection in a manner analogous to that used in the preparation of Intermediate B, the Y2XA Intermediates.

Step 5:

Reaction of Intermediates Υ 2 ΧΆ in a manner analogous to that used for the preparation of [(15,2R, 35,4R) -4- (2-chloro-6 - {(R) -1- [9 - ((1R, 25,3R, 45) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -95-purin-2-yl ] -pyrrolidin-3-ylamino} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -carbamic acid tert-butyl ester (Example 1, Step 1), each using the corresponding Intermediate X2A, Intermediate X2YB.

Wherein Xd is selected from

Step 6:

Intermediates X2YB are reacted in ethanol at reflux, or in DMSO at 90-110øC for 18-24 hours individually with a 3X excess of the appropriate Intermediate Z (as described above). Examples of formula (III) are isolated after purification by mass directed reverse phase chromatography. 70 ΡΕ2066669

The Examples of the formula (III) are prepared as described below.

Intermediates YXC are reacted in acetonitrile / N-methylpyrrolidone in the presence of sodium iodide, triethylamine, individually with the T-H amines. Heating with microwave radiation at temperatures of 120-220 ° C yields the series of Examples of formula (III).

Amines T-H

71 ΡΕ2066669

The Examples of the formula (IV) are prepared as described below.

These examples are prepared from Intermediates X2YB in a manner analogous to that used to prepare the Examples of formula (III).

The Examples of the formula (V) are prepared as described below.

Scheme 4 K '&lt; Eur-lex.europa.eu eur-lex.europa.eu ; '..................... (1) and (2), and (b)

These examples are prepared from Intermediates YXA2 in a manner analogous to those of the examples of formula (III). Intermediates YXA2 are prepared from Intermediates YX in a manner analogous to that used in the preparation of Intermediate 1, substituting (3 R) - (+) - (3-Boc-amino) pyrrolidine for the appropriate protected amine (Boc ) -AH.

Amines protected with Boc, (Boc) -A-H: VSs, (NH) 0 - Q ΧΧλ, NH 4 π & & & & & & & & & & & & & & & & & & & & &.

A Binding Agents:

73 ΡΕ2066669

Intermediate K is converted to Example V in a manner analogous to Example I.

The Examples of the formula (VI) are prepared as described below.

Scheme 5, and FIGS. 5A and 5A show a cross-sectional view of FIG.

These examples are prepared from Intermediates Χ2ΥΆ2 in a manner analogous to those of the formula (III). Intermediates X2YA2 are prepared from Intermediates X2Y in a manner analogous to that used for the preparation of Intermediate B, substituting (3r) - (+) - (3-Boc-amino) pyrrolidine for the appropriate Boc-protected amine , (Boc) -AH. 74 ΡΕ2066669

Examples of Ribose

These Examples are prepared with formula (VII) as described below.

(VII)

Scheme 6

STEP

. (YW et al., Proc. Natl.

VV γ * fc,

Vv. · 1 &quot;

Κ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ Η ϊ ϊ ϊ Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η

Λ ** V · b bT

* V · ννν- · -! [ΥΥ] W0- $ S8 $ tôTO PÃSSS? 5 ', 4'-methoxy-2'

TV Y &quot; »

fVJ Έ Έ w f y y Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ

Step 1:

(2R, 5R) -4-Acetoxy-2- (2,6-dichloro-purin-9-yl) -5- (2-ethyl-2 H -tetrazol-5-yl) -tetrahydro- furan-3-yl ester (WO 98/28319) in DCE at 50 ° C with the appropriate amine YH, in the presence of DIPEA are obtained the RY Intermediates.

Step 2:

The RY Intermediates are deprotected using potassium carbonate in MeOH / chloroform at room temperature to give the RY1 Intermediates.

Step 3:

Reaction of the RY1 Intermediates individually with the appropriate Boc-protected amine, (Boc) -A-H, followed by deprotection in a manner analogous to that used in the preparation of Intermediate B, the Intermediates RY1A are obtained.

Step 4:

(2R, 5R) -4-Acetoxy-2- (2,6-dichloro-purin-9-yl) -5- (2-ethyl-2 H -tetrazol-5-yl) (WO 98/28319) under conditions analogous to those described in Steps 1 and 2, RY1A2 Intermediates are obtained. 76 ΡΕ2066669

Step 5:

Intermediates RY1A2 are reacted with acetonitrile / N-methylpyrrolidone in the presence of sodium iodide, triethylamine, individually with the T-H amines. Heat with microwave radiation at temperatures of 120-220 ° C to give the series of Examples of formula (VII).

The Examples of the formula (VIII) are prepared as described below.

Scheme 4 v

These examples are prepared from Intermediates X 2 Y 2 in a manner analogous to the examples of formula (III). Intermediates X2YA2 are prepared from 77æ2066669 of Intermediates X2Y in a manner analogous to that used in the preparation of Intermediate B, substituting (3R) - (+) - (3-Boc-amino) pyrrolidine for the Boc-protected amine (Boc) -AH.

Amines protected with Boc, (Boc) -A-H:

Resultant Binding Agents: '' 'brtx \'

A N *.

XX

Intermediate L in Example VIII is converted in a manner analogous to that used for Example I.

The Examples of the formula (IX) are prepared as described below. ΡΕ2066669 78

- - - - - - - - - - - - - - - - - - - - - - - - - - -

Scheme 5:

These examples are prepared as follows:

Step 1: Intermediates YXBA2 are prepared from Intermediates YX in a manner analogous to that used in the preparation of Intermediate B, substituting (3R) - (+) - (3-Boc-amino) pyrrolidine for the appropriate Boc-protected amine , (Boc) -AH.

Step 2: By reaction of YXBA2 Intermediates in an analogous manner to that used to prepare [(1S, 2R, 3S, AR) -4- (2-chloro-6 - {(R) -1- - [(1R, 2S, 3R, S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9,7-purin-2-yl] -pyrrolidin-3-ylamino} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -di-carbamic acid tert-butyl ester (Example 1, Step 1), using the corresponding Intermediate X2A individually, Intermediates M. 79 ΡΕ2066669

Step 3: Intermediates M are reacted in acetonitrile / N-methylpyrrolidone in the presence of sodium iodide triethylamine, individually with the T-H amines. Heating with microwave radiation at temperatures of 120-220 ° C yields the series of Examples of formula (IX).

Boc-protected amines, (Boc) -A-H, the resulting binding agents A, and the T-H amines are as described above.

Lisbon, December 13, 2010

Claims (6)

A compound of formula (Ia), or stereoisomers thereof, or the pharmaceutically acceptable salts of these compounds, in which R 1 and R 1b are independently selected from a 3- to 12-membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur, the said group being optionally substituted with oxo, O-C 1 -C 6 alkyl, C 1 -C 10 aryl, R 1 c or with C 1 -C 8 alkyl optionally substituted with OH, or R 2 and R 1 are independently selected from -NR 4 R 4, and -NR 5 C 1 -C 8 -alkylcarbonyl; R 2 is C 1 -C 8 alkyl optionally substituted with OH, aryl C 1 -C 8 aryl optionally substituted with OH, S-C 1 -C 8 alkyl, CN, halogen, O-C 7 -C 14 aralkyl, or O-C 1 -C 6 alkyl, a carbocyclic group C3 -C15 -alkyl optionally substituted with C7 -C14 O-aralkyl, C3 -C15 carbocyclic group, O-C1 -C8 alkyl, C2 -C8 alkenyl, C2 -C8 alkynyl or C1 -C8 alkyl, O-C1 -C8 alkyl, -SO2 -C1-8 alkyl, a 3- to 12-membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing further 1-4 heteroatoms selected from the group consisting of oxygen and sulfur, which group is optionally substituted with a 3- to 12-membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing further 1-4 heteroatoms selected from the group consisting of oxygen and sulfur, C7 -C14 aralkyl, or C6 -C14 aryl optionally substituted with O C7-C14 aralkyl, or R3 is hydrogen, halo, C2-C8 alkenyl C1 -C8 alkoxy, C1 -C8 alkoxy or C1 -C8 alkoxycarbonyl, or R3 is optionally substituted C1 -C8 alkylamino optionally substituted with OH, R1, amino, di (C1 -C8) alkylamino, -NH- C (= O) -C 1 -C 8 alkyl, -NH-SO 2 -C 1 -C 8 alkyl, -NH-C (= O) -NH-R 3 c, -NH -C (= O) -NH- C 3 -C 15 carbocyclic group or with C 6 -C 10 aryl optionally substituted with C 1 -C 10 aryloxy, or R 3 is a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heterocyclics selected from the group consisting of oxygen and sulfur, which group is optionally substituted with 0-3 R4; R and R are each independently a 3- to 12-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; optionally substituted with halo, cyano, oxo, OH, carboxyl, nitro, C1 -C8 alkyl, C1 -C8 alkylcarbonyl, OH-C1 -C8 alkyl, C1 -C8 haloalkyl, aminoC1-8 alkyl, amino (OH) C 1 -C 8 -alkoxy or C 1 -C 8 -alkoxy optionally substituted with amino-carbonyl; R 3c is a 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur which is optionally substituted with a 5- or 6-membered heterocyclic group containing at least one an ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; R are independently a 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, a 5- or 6-membered heterocyclic group which is optionally substituted with halo, cyano, oxo , OH, carboxy, amino, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkylsulfonyl, aminocarbonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy optionally substituted with aminocarbonyl, or a 5- or 6-membered heterocyclic ring containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, which ring is also optionally substituted with halo, cyano, oxo, OH, carboxyl, amino, nitro, C1 -C6 alkyl, C1 -Cs alkylsulfonyl, aminocarbonyl, -Cs-carbonyl, C1 -C6 alkoxy optionally substituted with aminocarbonyl; R4 is selected from OH, C1 -C8 alkyl optionally substituted with OH, C1 -C6 alkoxy, C7 -C14 aralkyl optionally substituted with OH, O-C1 -C8 alkyl, C6 -C10 haloaryl, or O-aryl C6 -C10 alkoxy, C6 -C10 alkoxy optionally substituted with OH, C1 -C8 alkyl, O-C1 -C8 alkyl or -halo, O-C6 -C10 aryl optionally substituted with OH, C1 -C8 alkyl, O C 1 -C 8 -alkyl or -halo, and NR 4 C (O) NR 9 R 4 h; R4f, R4h are independently H, or C1-C8alkyl; R4g is a 3- to 12-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; and A is selected from 6 ΡΕ2066669 A compound according to claim 1, for use as a drug. A compound according to claim 1, together with an anti-inflammatory, bronchodilator, antihistaminic or antitussive pharmaceutical substance, said compound and said pharmaceutical substance being in the same pharmaceutical composition, or in compositions pharmaceutical companies. A pharmaceutical composition comprising as active ingredient a compound according to Claim 1, optionally together with a pharmaceutically acceptable diluent or carrier. The use of a compound according to Claim 1 for the manufacture of a medicament for the treatment of an inflammatory or obstructive airway disease. A process for the preparation of compounds of formula (I) as defined in Claim 1, or stereoisomers thereof or pharmaceutically acceptable salts thereof, comprising the steps of: (a) the compound of formula (II) (H) wherein R 1a, R 1b, R 2, U 1, U 2 are as defined above in this document; and T is an leaving group, with a compound of formula (III) H-R 3 (III), wherein R 3 is as defined hereinbefore; and (ii) any protecting groups are removed and the resulting compound of formula (II) is recovered in its free form or that of a pharmaceutically acceptable salt. Lisbon, December 13, 2010